This project is central to the Conte center. All other projects are linked to this project in a conceptual and a practical sense. This project follows up on our findings that lesions disrupt the functioning of the mood circuit in elderly patients with depression. The project utilizes multimodal imaging Diffusion tensor imaging (DTI), magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS) along with cognitive testing and genetics to study the connectivity and dysregulation of the mood circuit. Based on findings from our earlier work we evaluate the nature of the changes in the fiber tracts connecting amygdala, Orbital prefrontal cortex, dorsolateral prefrontal cortex, striatum and its relationship to neurocognitive changes. We evaluate whether glutamate is reduced in the anterior cingulate and orbital prefrontal cortex in patients with depression using MRS. In addition we evaluate changes in brain structure and function as it relates to serotonin transporter promoter region allelic variants. This project uses state of the art image processing and will lead to a greater understanding of the neuroanatomical substrates of depression.